The research described in this proposal will provide evidence that is crucial for the possible development of a highly specific immunotherapy in patients with multiple sclerosis (MS). Although the cause and mechanisms of pathogenesis of MS are unknown, there is increasing evidence to implicate autoimmunity, namely that broad spectrum immunosuppressive drugs can slow the disease process in many patients. Currently the best candidate for a target autoantigen in MS is myelin basic protein (BP), although other central nervous system antigens have not been eliminated from consideration. BP has been sequenced, and is known to induce a wide spectrum of clinical manifestations on different genetic backgrounds, similar to MS. During the last granting period, we found that MS patients had a higher frequency and magnitude of T cell responses to the 45-89 sequence of BP than controls. The only definitive way to assess the importance of T cell responses to disease-associated BP epitopes in patients. We have demonstrated previously that T lymphocytes that cause experimental autoimmune encephalomyelitis (EAE) in rats utilize common V region genes in their receptors (TCR) specific for BP. Because of the common peptide sequences coded for by these TCR V genes, we have been able to protect animals from EAE by vaccinating with synthetic peptide sequences from the TCR. Immunization with TCR peptide in MS patients would now appear to be feasible and safe if BP reactive T cells in humans utilize common TCR genes. This is precisely the focus of the current grant. Specifically, the proposed experiments will isolate and characterize BP- specific T cell clones, and will identify common variable region genes used in the rearranged alpha and beta chains of the TCR of BP-specific clones. Early results indicate that common genes are present. If so, the relevant TCR peptides can be identified for use in a clinical trial. Thus, the current proposal is the critical link between a very successful approach for the selective regulation of EAE and the opportunity to test definitively the hypothesis that autoimmunity to BP contributes to the pathogenesis of MS.